Providing adequate nutrition via the parenteral route requires administration of both lipids and carbohydrates in sufficient quantities within an acceptable volume of solution. Most technical problems have been solved in conjunction with the administration of lipids. This is evidenced by products such as Liposyn fat emulsion which can deliver the required number of fat calories. However, administration of the desired number of carbohydrate calories via the peripheral route remains inadequate. The main reason is that an isotonic solution of glucose such as 5% dextrose only delivers 170 Kcal/liter, while the desired daily regime is 850 Kcal/liter. One may consider three alternatives:
1. Increase the volume of solution by 5 times. This is obviously unacceptable, as the total volume of fluid permitted per day is 3 liters.
2. Increase the concentration of the solution by 5 times. This results in a hypertonic solution which would damage peripheral veins when administered intravenously.
3. Use a polymer of glucose. This has been studied and possesses the advantage of delivering 3-7 glucose units in one molecule, thereby increasing the theoretical caloric content while maintaining an isotonic osmolarity solution.
One limitation of using such a glucose polymer is that the human body apparently has a limited capacity to hydrolyze efficiently the glycosidic linkages which interconnect the glucose units. This results in a loss of calories as a consequence of excretion of polymer fragments such as maltose in the urine.
It has now been found that this problem of limited hydrolysis and excretion can be circumvented by using hybrid ester oligomers and/or polymers of the general formula: ##STR1## wherein n is an integer of 1 to 20 and R is hydrogen or an alkyl or alkenyl group having 1 to 20 carbon atoms. The ester linkages coupling the glucose and malonate units in I may be at any of the available glucose hydroxyl functions and may vary within different glucose units of a given polymer or polymer mixture. Those compounds where the alkyl or alkenyl group carbon has an even number of carbon atoms are preferred. Compounds of the foregoing formula have the advantage of providing ester linkages which are readily hydrolyzed by esterases widely distributed in human tissues.
These malonic acid derivatives were chosen because they would be decarboxylated in vivo through enzymes like palmitate synthetase which exists in vertebrates. This is illustrated as follows: ##STR2## wherein I is as previously stated and R is the same in Formulae I and II. The product of decarboxylation (II) is a natural fatty acid; therefore, a nontoxic food constituent which also can provide considerable caloric value.
The choice of the R substituent provides flexibility in adjusting the total caloric content from the lipid part. For example, R could be an unsaturated fatty acid side chain of sufficient carbon atoms so that linoleic acid results from decarboxylation, if this feature is of advantage in the diet of the recipient. The number of glucose units provides flexibility from the carbohydrate standpoint.
Another advantage of the compounds of this invention are their low toxicity. For example, di-(1,1'-D-glucopyranosyl)ethylmalonate, when tested in mice, exhibited an LD.sub.50 of 9.70 g/kg.
The compounds as represented by Formula I may be prepared readily from known materials. Compounds containing two glucose moieties and one malonate unit (Formula I, n=1) can be prepared by reacting an appropriately protected monohydroxy glucose with an activated malonic acid derivative wherein R is stated in Formula I to give a protected malonyl diester which, upon subsequent removal of the glucose protecting groups, affords the desired diglucosyl malonate (Formula I, n=1) as outlined below: ##STR3##
For such reactions, benzylether substituted monohydroxyglucose derivatives (R'=CH.sub.2 -phenyl) are preferred as they can be removed under neutral catalytic hydrogenolysis conditions, however, other substituted glucose derivatives may be utilized providing the protecting groups can be removed under conditions which do not cleave the glucose-ester bond. Such protected derivatives will be evident by those skilled in the art.
Compounds containing three glucose units and two malonate derivatives (Formula I, n=2) may be prepared by condensing two moles of a protected glucosyl malonate monoester with one mole of a suitably protected dihydroxyglucose, followed by removal of glucose protecting groups under mild conditions as indicated by the following equation: ##STR4##
The required glucosylmalonate monoesters are prepared readily from a suitably protected monohydroxy glucose and a malonate monoester derivative such as 2,2,2-trichloroethyl malonate, followed by selective removal of the nonglucosyl ester as shown below: ##STR5##
Preferred esterification conditions for these condensations are a modification of the carbodiimidedimethylaminopyridine procedures described by B. Neises and W. Steglich, Angew. Chem. Int. Ed. Engl. 1978, 17, 522-524 and by A. Hassner and V. Alexanian, Tetrahedron Lett. 1978, 4475-4478.